review tandem catalysis: a taxonomy and illustrative...

Coordination Chemistry Reviews 248 (2004) 2365–2379

Review

Tandem catalysis: a taxonomy and illustrative review

Deryn E. Fogg∗, Eduardo N. dos Santos∗,1

Department of Chemistry and Center for Catalysis Research and Innovation, University of Ottawa,10 Marie Curie, Ottawa, ON, Canada K1N 6N5

Received 2 February 2004; accepted 18 May 2004Available online 6 August 2004

Contents

Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23661. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23662. Taxonomy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2366

2.1. Processes that are not tandem catalyses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23662.1.1. One-pot reactions involving isolated catalytic events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23662.1.2. Domino reactions involving one catalytic elaboration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23662.1.3. Domino (cascade) catalysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2367

2.2. Tandem catalysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23672.2.1. Orthogonal tandem catalysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23672.2.2. Auto-tandem catalysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23682.2.3. Assisted tandem catalysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23682.2.4. Summary of relative merits. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2368

2.3. Related processes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23692.3.1. Multifunctional catalysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23692.3.2. Multicomponent catalysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23692.3.3. Combinatorial catalysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2370

3. Review of tandem catalytic processes involving olefin metathesis or hydroformylation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23703.1. Scope of review. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23703.2. Tandem catalyses involving olefin metathesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2370

3.2.1. Metathesis-hydrogenation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23703.2.2. Metathesis-ATRP-hydrogenation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23733.2.3. Metathesis-isomerization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23733.2.4. Metathesis-Heck coupling. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2374

Abbreviations: ADMET, acyclic diene metathesis; ATRP, atom-transfer radical polymerization; CM, cross-metathesis; COE, cyclooctene; COD,1,5-cyclooctadiene; dba, dibenzylideneacetone; e.e., enantiomeric excess; en, ethylenediamine; H2IMes, N,N′-bis(mesityl)imidazolin-2-ylidenes; IMes,N-N′-bis(mesityl)imidazol-2-ylidene; MA, methyl acrylate; MMA, methyl methacrylate; NBD, norbornadiene; NHC,N-heterocyclic carbene; phen,1,10-phenanthroline; RCM, ring-closing metathesis; ROM, ring-opening metathesis; ROMP, ring-opening metathesis polymerization; THF, tetrahydrofuran

∗ Corresponding authors. Tel.:+1 613 5625800x6057/+55 31 34995743; fax:+1 613 5625170/+55 31 34995700.E-mail addresses:[email protected] (D.E. Fogg), [email protected] (E.N. dos Santos).1 On sabbatical leave from Departamento de Quı́mica—ICEx, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, Brazil.

0010-8545/$ – see front matter © 2004 Elsevier B.V. All rights reserved.doi:10.1016/j.ccr.2004.05.012

2366 D.E. Fogg, E.N. dos Santos / Coordination Chemistry Reviews 248 (2004) 2365–2379

3.3. Tandem catalyses involving hydroformylation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23743.3.1. Hydroformylation-Mukaiyama cyclization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23743.3.2. Hydroformylation–carbonylation (amidocarbonylation). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23743.3.3. Hydrogenation–hydroformylation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23753.3.4. Hydroformylation–hydrogenation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23753.3.5. Isomerization–hydroformylation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23763.3.6. Double-tandem processes involving hydroformylation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2377

4. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2377Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2378References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2378

Abstract

A scheme is advanced for the classification of one-pot, coupled catalytic transformations, which distinguishes between one-pot, domino/cascade, and tandem catalysis. The last of these is divided into three subclasses: orthogonal, auto-tandem, and assisted tandem catalysis. Theproposed taxonomy, and the potential of tandem catalysis in organic synthesis, are illustrated with examples drawn from olefin metathesisand hydroformylation chemistry.© 2004 Elsevier B.V. All rights reserved.

Keywords:Catalysis; Tandem catalysis; Classification; Cascade catalysis; Domino catalysis; Orthogonal catalysis; Olefin metathesis; Hydroformylation

1. Introduction

Devising methodologies for elaboration of simple precur-sors into complex molecular targets is the underlying themein much of synthetic organic chemistry. While transition-metal catalyzed processes have enabled transformative de-velopments in organic synthesis, the power and efficiencyof such methods are limited by the conventional focus onchemical reactions as discrete events. Much interest hastherefore attached to “one-pot” processes involving multiplecatalytic transformations followed by a single workup stage.Motivating their development is the continuously-expandingimportance in organic chemistry of highly selective transfor-mations mediated by well-defined transition metal catalysts,and the potential process and catalyst efficiencies associ-ated with coupling such transformations[1].The increasingpopularity of processes harnessing coupled catalysis is high-lighted by the number of recent reviews in this area. Espe-cially well-documented is work on Pd-catalyzed C–C bondformation[2–7]; such processes are well represented in a re-cent Handbook[8]. Other reviews describe coupled metathe-sis [9–11] or hydroformylation[12,13] catalysis, enzyme-[14,15]or nickel-catalyzed[16] domino reactions, and mul-tifunctional [17,18]or multicomponent catalysis[17,19]; insome cases, a section on catalysis is included in a broadersurvey of stoichiometric tandem or cascade reactions[1,20–22]. In surveying the literature, however, it becomesrapidly evident that a general review is hampered by the in-terchangeable use of near-synonymous terms: among them,tandem, domino, zipper, multifunctional and cascade reac-tion or catalysis. Moreover, the existing terminology drawsno consistent line of demarcation between multiple catalytic,versus stoichiometric, transformations. This blurs mechanis-tic distinctions, to the detriment of informed exploration oruse. With the intention of clarifying the current state of thefield, as well as revealing possibilities currently obscured,

we propose a brief taxonomy, or classification scheme, withwhich to codify this increasingly important area.

2. Taxonomy

One-pot procedures involving multiple catalytic eventsconstitute a subset of the broader category of one-pot pro-cesses that includes domino, cascade, or tandemreactions.All of these terms are commonly used to designate transfor-mation of an organic substrate through two or more individ-ual elaborations with a single workup step[1,5,15,20,23], asense we shall build on in constructing a parallel terminol-ogy for coupled catalyses. For clarity, we begin by definingone-pot catalytic processes that arenot tandem catalyses.

2.1. Processes that are not tandem catalyses

2.1.1. One-pot reactions involving isolated catalytic eventsModification of an organic moiety via two catalytic elab-

orations, with addition of the second catalyst only after thefirst catalytic transformation is complete, is not a tandemcatalysis, but a one-pot (bicatalytic) reaction. We definedomino and tandem catalyses, in contrast, as having all cat-alytic species—whether masked or apparent—present fromthe outset.

2.1.2. Domino reactions involving one catalytic elaborationA one-pot sequence consisting of a single catalytic trans-

formation and a subsequent stoichiometric modification doesnot constitute a tandem catalysis, even though the substratehas undergone two distinct transformations. Such a processmay be classified as a domino reaction (providing that allreagents are simultaneously present, vide infra), but a mono-catalytic event. The reactions described in the following sec-tions involve sequential elaborations of an organic substratevia multiple catalytic transformations. A flowchart is pro-vided inFig. 1 to aid in classification.

D.E. Fogg, E.N. dos Santos / Coordination Chemistry Reviews 248 (2004) 2365–2379 2367

Fig. 1. Flowchart for classification of one-pot processes involving sequen-tial elaboration of an organic substrate via multiple catalytic transforma-tions.

2.1.3. Domino (cascade) catalysisTietze defines a domino reaction as involving “two or

more bond-forming transformations which take placeunderthe same reaction conditions, without adding additionalreagents and catalysts, and in which the subsequent reac-tions result as a consequence of the functionality formed inthe previous step”[1] (italics added). Faber adds that thesequential processes are not readily intercepted, i.e. inter-mediates are not generally isolable[15]. We adopt theseproposals for domino catalysis, in which we further stip-ulate that (in contrast with tandem catalysis, see below),multiple transformations are effected via asinglecatalyticmechanism. Sequential elaborations may be effected ineither intermolecular processes (involving release of inter-mediates from the catalytic cycle) or intramolecular pro-cesses;Fig. 2. Cascade catalysis is a virtually synonymousterm, reserved for multiple (≥3) domino sequences. Manycoupled catalytic processes are of the domino/cascade type,and many beautiful examples (see, for example,Scheme 1[24]) have been reported.

Fig. 2. Schematic illustration of domino catalysis: (a) intermolecular; (b)intramolecular.

2.2. Tandem catalysis

We reserve the term tandem catalysis to describe coupledcatalyses in which sequential transformation of the substrateoccurs via two (or more) mechanistically distinct processes.

Scheme 1. Example of intramolecular domino (cascade) catalysis in the synthesis of a polyspirane via Pd-catalyzed cycloisomerization of a polyenyne [24].

Fig. 3. Schematic illustration of orthogonal catalysis. (*Additional reagent,if required, must be present from the outset of reaction.)

Scheme 2. Example of orthogonal tandem catalysis in the synthesis offenestranes via tandem allylic alkylation—Pauson–Khand catalysis[27].

We draw on two of the accepted meanings for the wordtandem: (a) “an arrangement of two [mechanisms] workingin cooperation”, and (b) “one after the other”[25]. Threecategories may be distinguished: orthogonal, assisted, andauto-tandem catalysis, as indicated in the Flowchart. Advan-tages and disadvantages of each, noted within the followingsections, are summarized inSection 2.2.4.

2.2.1. Orthogonal tandem catalysisOrthogonal reactions are characterized by their mutual

independence. Orthogonal tandem catalysis, by analogy, in-volves two or more functionally distinct and (in principle)noninterfering catalysts or precatalysts, all of which arepresent from the outset of reaction.Fig. 3 depicts such aprocess, in which an organic starting material (Substrate A)undergoes preferential reaction with Catalyst A to generateProduct A, which in turn functions as Substrate B (the sub-strate for Catalyst B). A stoichiometric reagent may also beused to convert Product A into Substrate B. In orthogonalcatalysis, the two catalytic cycles operate simultaneously,once Substrate B is generated (though the organic startingmaterial undergoessequentialchange).

Limitations of such catalytic methodologies[17,26] in-clude inefficient catalyst utilization, compounded by diffi-culties in recovering individual precious metal components,possible negative interactions between the catalysts used toeffect the independent transformations, and the likelihoodthat one set of reaction conditions is not optimal for bothcatalytic processes.


Fig. 4. Schematic illustration of auto-tandem catalysis. (*Additionalreagent, if required, must be present from the outset of reaction.)

Scheme 2shows an example of orthogonal tandem cataly-sis in ene–yne elaboration to yield fenestranes[27]: the firstPauson–Khand reaction is not part of the tandem catalysis, asthe Pd catalyst is added only once this step is complete. An-other elegant example of orthogonal catalysis was recentlydeployed in synthesis of branched polyethylenes[28].

2.2.2. Auto-tandem catalysisProcesses of this type involve two or more mechanistically

distinct catalyses promoted by a single catalyst precursor:both cycles occur spontaneously by cooperative interactionof the various species (catalyst, substrate, additional reagentsif required) present at the outset of reaction. No reagentsbeyond those originally present need be added to trigger thechange in mechanism. Entry into both cycles is presumed tobe mediated by a catalyst species in which the structure isessentiallyconserved, though intermediates will necessarilydiffer at points in each cycle. In the first mechanism (Fig. 4),Catalyst A acts on Substrate A to convert it to Product A.Product A functions as Substrate B, entering the second typeof catalytic transformation mediated by Catalyst A (or A′).As in orthogonal tandem catalysis, auto-tandem processesare (ideally) sequential in terms of transformation of a givenmolecule of substrate, but they are normally concurrent in amacroscopicsense. That is, Cycle B operates simultaneouslywith Cycle A, once Product A is generated.

Auto-tandem catalysis can be difficult to control, and in-deed processes of this type (whether recognized or not)are commonly responsible for side-reactions in catalysis.This is especially true where Substrate A can itself en-ter into both catalytic cycles (as, for example, in tandemaldol-hydrogenation catalysis of acetone, in which acetonehydrogenation competes with its self-condensation[29]).A more fundamental difficulty, as in orthogonal catalysis,emerges from the likelihood that the conditions for optimalperformance differ for the two catalytic processes. Wherethe appropriate balance can be found, however, auto-tandemcatalysis are exceptionally efficient, as evidenced by the suc-cess of the Shell Oxo Process, the most important industrialapplication of this methodology[30] (seeSection 3.3). Anexample of auto-tandem catalysis is given inScheme 3 [31].

2.2.3. Assisted tandem catalysisThe range, performance, and selectivity of transforma-

tions that can be effected by a single catalyst species can beexpanded by addition of a further reagent to trigger a changein mechanism, a process we term assisted tandem catalysis.Fig. 5illustrates the process: Catalyst A is permitted to carry

Scheme 3. Auto-tandem catalysis: synthesis of esters from acid chloridesvia sequential (homogeneous) Rosenmund–Tishchenko catalysis (L: PPh3)[31].

Fig. 5. Schematic illustration of assisted tandem catalysis. (*Additionalreagent may or may not be required.)

out one function, and is then transformed (often by directmanipulation of the active site) into Catalyst B, which thenacts on the product of the original catalytic cycle. In contrastwith orthogonal and auto-tandem catalyses, the two catalyticprocesses cannot occur simultaneously, as the two catalystsdo not coexist. An example of assisted tandem catalysis isshown inScheme 4 [32].

From the perspective of the benchtop chemist, the princi-pal limitation of assisted tandem catalysis is the requirementfor intervention. In contrast to orthogonal and auto-tandemcatalysis, the coupled transformations do not proceed spon-taneously, and the reaction must be monitored in order todetermine when the first process is complete, so that thesecond is not triggered prematurely. Of greater significancein industrial practice may be any increase in time or energyrequirements associated with the temporal split in the twoprocesses.

2.2.4. Summary of relative meritsAdvantages and disadvantages of the different forms of

tandem catalysis are summarized inTable 1. This should beregarded as a general guide, however, as individual excep-tions can be envisaged for each parameter considered. Thevarious parameters are clarified with some brief commentsbelow.

An advantage common to all of these processes is thehigh efficiency associated with elimination of intermediateworkup steps. However, auto-tandem and assisted tandemcatalyses, which make multiple use of a single (pre)catalyst,

Scheme 4. Example of assisted tandem catalysis: Pd-catalyzed bromoal-lylation and Sonogashira cross-coupling[32].


Scheme 5. Multifunctional catalysis in the catalytic asymmetric Michael reaction, with structure of proposed intermediate[41].

Table 1Relative merits of different classes of tandem catalysis

Consideration Orthogonal Auto Assisted

Workup efficiency High High HighEfficiency in catalyst utilization Poor High HighProcess efficiency High High LowCapacity to optimize conditions

for both catalysesLimited Limited High

Capacity to control selectivity Limited Limited HighInteraction between catalysts

effecting different reactionsPossible Minimal None

Ease of catalyst recovery Poor Good Good

are more efficient in catalyst utilization than orthogonalcatalysis, which requires a different catalyst for each trans-formation. Process efficiency, in terms of utilization of timeand energy, is higher for orthogonal and auto-tandem catal-ysis, in which both transformations occur under a single setof reaction conditions, without any need for monitoring orintervention. Against this, however, must be set the inabil-ity to optimize reaction conditions for each catalytic pro-cess. Assisted tandem catalysis has a lower overall processefficiency, but the fact that reaction conditions can be op-timized for each process increases the capacity to optimizeselectivity in each transformation.

Interaction between different catalyst species is poten-tially problematic in orthogonal catalysis, in particular.While ideally the catalyst species do not interfere, in prac-tice interplay between them can be common. This is less ofa concern for auto-tandem catalysis, in which the catalystspecies are closely related. Because the different catalyticprocesses occur simultaneously, however, some potentialfor negative interaction may exist. In assisted tandem catal-ysis, interaction is precluded because the different catalystspecies do not coexist.

Finally, “ease of catalyst recovery” is considered for com-parison ofhomogeneouscatalyst systems only, and describesthe relative difficulty in catalyst recovery, separation, andreuse. In using a mixture of catalysts (as in orthogonal tan-dem catalysis), recovery is complicated by the need to sep-arate the metal complexes.

2.3. Related processes

For completeness, we include definitions for several re-lated catalytic processes, which are generally, though notinvariably, distinct from tandem catalysis.

Fig. 6. Schematic illustration of one possible (concerted) mode of oper-ation for a bifunctional catalyst[18].

2.3.1. Multifunctional catalysisIn homogeneous, heterogeneous, and enzyme catalysis,

multifunctional catalysis is overwhelmingly held to be aprocess in which two or more active sites, linked together,act synergicallyto effect one or more transformations of asubstrate[17,33–36].2 This sense is highlighted in recentreviews of multifunctional homogeneous catalysis[18,37],one of which[37] undertakes further classification accordingto type of synergic interaction. Countering this precedent isthe emerging use of this term (by one of us[38], among oth-ers[39,40]) to describe non-synergic procedures that wouldpreferably be classified as assisted or auto-tandem catalysis,or indeed to describe catalysts that simply have thepotentialto carry out multiple catalytic functions. Finally, we note thatthe related term “multifunctional initiator”, used in polymerchemistry, refers to a species with multiple, usually identical,initiating sites. Schematic and exemplary representations ofmultifunctional catalysis, in the most broadly accepted sensenoted above, are given inFig. 6andScheme 5, respectively.

2.3.2. Multicomponent catalysisHesse[17,42]defines a multicomponent catalyst as a mix-

ture of two or moremonofunctional catalysts. (Again, wheresuch a mixture of catalysts effects sequential catalytic trans-formations of the substrate, the process can be recognizedas orthogonal tandem catalysis.) In practice, however, theterm “multicomponent” is widely applied to catalyst sys-tems containing, in addition to an active catalyst species,stoichiometric additive(s) that modulate catalytic properties.In other examples (as indeed in the classic Wacker Processfor oxidation of ethylene to acetaldehyde[43]), the organicproduct is generated by cooperative interaction of several(co)catalyst species, but only one of these acts directly on

2 Where consecutive catalytic transformations of substrate are effectedin a synergic fashion (that is, where Weisz’s “intimacy criterion”[36]enables rapid diffusion of intermediates between the two sites), multi-functional catalysis can be seen as a subset of auto-tandem catalysis.


Scheme 6. Multicomponent catalysis: allylic oxidation of limonene[44].

the substrate[19]. An example of this is shown inScheme 6.Such procedures are clearly not coupled catalytic processesof the type discussed in the preceding sections, in whicheach catalytic cycleeffects direct modification of the organicsubstrate.

2.3.3. Combinatorial catalysisCombinatorial methods in catalysis center around two dif-

ferent strategies: iterative “split-and-pool”, versus parallel,catalyst synthesis and screening[45–47].(Reetz notes thatthe term combinatorial is strictly applicable to split-and-poolmethods[48]; although a firm consensus on terminology hasnot been reached[49,50], the adjective “high-throughput”[47,51,52]is now often appended to parallel screening meth-ods). In neither case are “one-pot” coupled catalytic reac-tions typically explored at present. However, throughput hasbeen increased in certain cases[53,54] by screening a sin-gle catalyst against multiple substrates in one pot (Fig. 7,Scheme 7). Such a process may be termed one-pot parallelcatalyst screening.

Fig. 7. Schematic illustration of one-pot, parallel catalyst screening.

Scheme 7. One-pot, parallel catalyst screening for activity in ketonereduction[53].

3. Review of tandem catalytic processes involving olefinmetathesis or hydroformylation

3.1. Scope of review

In contrast with domino catalysis, the utility of whichis now well documented, tandem catalysis is only begin-ning to be exploited. While the current lack of consensus

on terms hampers a comprehensive review, the followingreview highlights opportunities presented by tandem cat-alytic methodologies in selected areas. The taxonomic prin-ciples proposed above are illustrated with synthetically use-ful examples drawn from the key areas of olefin metathesisand hydroformylation, each of which has spawned signifi-cant advances in tandem catalysis over the past five years.Additional examples may be found in a recent minireview[55].

3.2. Tandem catalyses involving olefin metathesis

While domino processes (including coupled ring-openingand ring-closing metatheses, reactions in which cross-metathesis is used to forestall ROMP, and clever ROM–RCM–CM sequences[9–11,56–58]) dominate coupledmetathesis catalyses, this area is also rich in examples oftandem catalysis. Many of these are of the assisted class,though the potential of auto-tandem catalysis is impliedby a recent review highlighting the richnon-metatheticalchemistry of the prototypical ruthenium metathesis catalystsshown in Fig. 8 [56], particularly the Grubbs catalyst1aand itsN-heterocyclic carbene (NHC) derivatives2. In thefollowing sections, processes are catalogued on the basis ofinitial reaction type, and subdivided according to class oftandem catalysis.

Fig. 8. Selected Ru metathesis catalysts.

3.2.1. Metathesis-hydrogenation

3.2.1.1. ROMP-hydrogenation.Ring-opening metathesispolymerization (ROMP) of cycloolefins, followed by hy-drogenation, enables synthesis of high molecular weight,narrow-polydispersity polyolefins[59–61]. The hydrogena-tion step is critical in order to eliminate the susceptibility tooxidative and thermal degradation, including crosslinkingreactions, associated with the olefinic linkages in the poly-mer backbone. While one-pot reactions in which metathesisis followed by addition of a stoichiometric or catalytic re-ducing agent remain common, considerable attention hasfocused on assisted tandem catalysis. In 1997, McLainet al. reported sequential processes of ROMP and hydro-genation of cyclooctene monomers using1b as precatalyst


Scheme 8. Synthesis of a functionalized polyethylene by assisted tandemROMP-hydrogenation of a cyclooctene monomer[59].

Scheme 9. Ru hydrides formed by hydrogenolysis of Grubbs metathesiscatalyst[62].

[59] (Scheme 8). Addition of H2 after metathesis was com-plete enabled the switch from metathesis to hydrogenationcatalysis, with near-quantitative polymer hydrogenationunder forcing conditions (135◦C, 400 psi H2). Subsequentmechanistic studies on1a [62] showed that such species un-dergo H2-hydrogenolyis of the Ru-alkylidene functionalityto liberate six-coordinate Ru(IV) dihydride5, accompaniedby its coordinatively unsaturated dihydrogen tautomer6(Scheme 9). Treatment with base effects transformationinto the more reactive hydridochloro species7 [62]. Indeed,addition of NEt3 enables reduction of ROMP polymers at30–100 psi H2 for precatalysts of type1 [60,61], as well asbimetallic Ru–alkylidene species[60]. Further increases inactivity were found on carrying out the reduction step withmethanol as cosolvent, this treatment generating highly ac-tive [63] hydrogenation catalyst RuHCl(CO)(PCy3)2 8 viacarbonylation of7. Thus, reduction of polyoctenes could beaccomplished at 1 atm H2 by adding NEt3, methanol, andH2 following ROMP of cyclooctene monomers in CH2Cl2[61]. Recent work indicates that other primary alcohols canconvert1a into 8 in the absence of added H2 [64].

Double-tandem cycles of ROMP–hydrogenolysis–ROMPor ROMP–hydrogenation–ROMP can be used to prepareunsaturated or saturated (respectively) polymer blends con-taining two distinct molecular weight fractions (Scheme 10)[61]. Such tailored blends can overcome processing prob-lems associated with narrow-polydispersity polymers. Theprocedure requires regeneration of a Ru–alkylidene follow-ing hydrogenolysis or hydrogenation of the ROMP polymerin CH2Cl2. Addition of propargyl chloride to the reac-tion solution effects transformation of7 into alkylidene1c[65], which can initiate a second cycle of ROMP to give

Scheme 10. Synthesis of tailored polymer blends via assisted double-tandem ROMP-hydrogenolysis-ROMP[61].

Scheme 11. Assisted tandem ADMET-hydrogenation[66,67].

the desired blend of two narrow-polydispersity polymers[61]. Polymer hydrogenation (at 250 psi) was also carriedout to obtain the saturated polymers, as above: the higherpressure is necessitated by the steric encumbrance of thepolynorbornene substrate, versus polyoctene.

3.2.1.2. ADMET-hydrogenation.Assisted tandem pro-cesses involving homogeneously catalyzed ADMET fol-lowed by heterogeneously catalyzed hydrogenation havebeen developed[66,67]. The protocol is extremely straight-forward, involving addition of silica and H2 followingmetathesis (Scheme 11). The need to separate the reducedpolymer from the silica support limits this approach topolymers that remain soluble following reduction. A sim-ilar heterogenization procedure might be advantageouslyapplied to (e.g.) RCM-hydrogenation, though no report tothis effect has yet appeared.

3.2.1.3. CM-hydrogenation, RCM-hydrogenation.Tan-dem metathesis-hydrogenation techniques have like-wise been applied to construction of small molecules(Scheme 12). While RCM (or CM)-hydrogenation chem-istry corresponds in many ways to ROMP-hydrogenation,some key differences result from differences in the cata-lysts typically used. CM and RCM generally require themore reactive Ru-NHC catalysts of type2, rather thanthe bis-PCy3 complexes1 typically used for Ru-catalyzedROMP. However, recent work suggests that the hydrogena-tion activity follows the opposite trend from metathesis:that is, Ru–NHC complexes are less hydrogenation-active

Scheme 12. Assisted tandem CM-hydrogenation in functionalization ofaryl chlorides[69].


Scheme 13. Assisted tandem RCM-hydrogenation in the synthesis ofcyclic dinucleotides[70].

Scheme 14. Assisted tandem RCM-hydrogenation in the synthesis ofmuscopyridine[71].

than their PCy3 analogues[68]. Also contributing tolower activity in the hydrogenation step in tandem RCM(CM)-hydrogenations is the higher dilution required to in-hibit competing ADMET, which effectively decreases theconcentration of the hydrogenation catalyst. These factorsoffset the greater reactivity of the olefinic groups in smallmolecules, versus macromolecular substrates, as well asthe higher catalyst loadings typically employed in RCMor CM (1–20 mol.% Ru, versus 0.5 mol.% for much of theROMP chemistry described above). The hydrogenation stepis therefore typically carried out at elevated temperaturesand H2 pressures (50–100◦C; 100–1000 psi H2; vide infra),although the conditions employed in some cases probablyreflect a target-focused procedure, rather than the mildestconditions required. It may be noted that the lower activityof the Ru-NHC catalysts can be advantageous in enhancingselectivity for less substituted C=C bonds[69].

In the first reported synthesis of small molecules via tan-dem metathesis-hydrogenation (Scheme 12), Grubbs andcoworkers applied1a and2b to CM-hydrogenation of acti-vated and unactivated alkenes, as well as to RCM-reductionof activated dienes containing cis, trans, conjugated, andtrisubstituted olefins[69]. Tolerance for amide, ester, arylchloride, and alcohol functionalities was demonstrated, aswell as the usual selectivity for hydrogenation of less sub-stituted olefins. This methodology has since been employedin construction of biologically relevant cyclic dinucleotides(Scheme 13) [70], as well as in a concise recent synthesisof (R)-(+)-muscopyridine via indenylidene catalyst3 [71](Scheme 14).

Tandem RCM-hydrogenation of diallyl ethers and dial-lylcarbinols (Scheme 15) has also been carried out at RTusing 2a “activated” for hydrogenation by addition of ca.15 mol.% NaH[72]. Reduction could be effected at 1–3 atmH2, or under argon in the presence of excess NaH and water.

Scheme 15. Assisted tandem RCM-hydrogenation in the synthesis ofaryltetrahydrofurans[72].

Scheme 16. Orthogonal tandem CM-hydrogenation[73].

3.2.1.4. Orthogonal CM-hydrogenation.Cossy’s grouphas employed orthogonal catalysis in tandem CM-hydroge-nation reactions using the Hoveyda catalyst4 and PtO2(Scheme 16) [73]. For experimental convenience, theentire sequence was performed under hydrogen atmo-sphere, necessitating use of a metathesis catalyst that re-sists hydrogenolysis. Under these conditions,4-catalyzedCM of allyl-triphenylsilane with �,�-unsaturated car-bonyl, carboxylic acid, or ester compounds is followed byPtO2-catalyzed hydrogenation, affording the saturated car-bonyl or carboxylic products in up to 75% yield. Competingreduction of the allylsilane is limited by use of a ratherunreactive hydrogenation catalyst: use of Pd/C resulted inpreferential reduction of allylsilane.

This methodology enables synthesis of substituted lac-tones and lactols via3-catalyzed CM-hydrogenation ofacrylic acid or acrolein with unsaturated alcohols, andspontaneous cyclization of the�-hydroxy acid or aldehydeproducts (Scheme 17) [74]. Unsaturated secondary alcoholsgave the target lactones or lactols in 45–70% yield. Thecorresponding unsaturated tertiary alcohols can give goodyields (up to 57%) of spirocyclic lactones using homoal-lylic alcohols: for sterically hindered substrates, however,reduction can dominate over CM.

3.2.1.5. CM(RCM)-ketone hydrogenation; CM(RCM)-alcohol oxidation. An elegant strategy reported by theGrubbs group exploits the capacity of RuHCl(en)LL’ species

Scheme 17. Synthesis of substituted lactones and lactols via orthogonaltandem CM-hydrogenation[74].


Scheme 18. Assisted tandem CM-transfer hydrogenation[69].

Scheme 19. Synthesis of (−)-muscone by assisted double-tandemRCM-transfer dehydrogenation–H2–hydrogenation procedure[69].

to promote regioselective transfer hydrogenation of thecarbonyl functionality in unsaturated ketones (Scheme 18)[69]. CM or RCM via 1a or 2b, followed by addition ofethylenediamine (en) and NaOH, was proposed to effectformation of RuHCl(en)(PCy3)(L) (L: PCy3, H2IMes), atransfer hydrogenation catalyst of the Noyori type. Selectivereduction of the ketone functionality was effected at roomtemperature in isopropanol under an atmosphere of H2.

Transfer hydrogenation could also be effected withoutaddition of the diamine, though more forcing conditionswere then required (80◦C). The reverse reaction, trans-fer dehydrogenation of alcohols to unsaturated ketones,was also carried out using 3-pentanone as proton acceptor.These methodologies were coupled in a beautiful exam-ple of double-tandem catalysis applied to the synthesis of(−)-muscone (Scheme 19) [69]. The product was obtainedin 56% yield by RCM of diene10, transfer dehydrogena-tion of the alcohol, and regioselective H2-hydrogenation ofthe olefin.

Scheme 20. Synthesis of diblock copolymers of polymethylmethacrylate and ethylene by double-tandem ROMP–ATRP-hydrogenation[75].

Scheme 21. Synthesis of cyclic enol ethers by assisted tandemRCM-isomerization[80].

3.2.2. Metathesis-ATRP-hydrogenationA double-tandem ROMP-ATRP-hydrogenation process

was devised using bifunctional catalyst1d (Scheme 20)[75]. The [Ru]=CHR site promotes both metathesis and(in conjunction with the 2-bromomethylpropionate initiatorthat terminates the alkylidene) ATRP. This system was usedto effect concurrent ROMP of cyclooctadiene (COD) andATRP of methyl methacrylate (MMA). The resulting di-block [COD]m[MMA] n copolymer was then hydrogenatedby exposure to H2 in toluene–THF. The cumulative processcan be classified as an auto-tandem ROMP-ATRP process,accompanied by an assisted tandem ROMP-hydrogenation.

3.2.3. Metathesis-isomerizationCompeting olefin isomerization can be problematic for

slow Ru-catalyzed RCM or CM reactions, particularly inaromatic solvents[69,76] and for NHC catalysts[76–79].Although it may be possible that the Ru-alkylidene itselfcan induce isomerization, a ruthenium hydride contami-nant or decomposition product is widely assumed to be theculprit. Snapper’s group has achieved controlled tandemRCM-olefin isomerization in five- to seven-membered ringsystems by adding a small proportion of H2 to promote iso-merization following RCM of acyclic dienes. Use of 95:5N2:H2 (forming gas) permitted isomerization with<10%hydrogenation. This strategy enabled synthesis of cyclicenol ethers (Scheme 21) [80], with the regiochemistry in allcases favouring the less substituted enol ether. Failure of theisomerization reaction in the absence of H2 indicates thata Ru-hydride catalyst is almost certainly involved, thoughattempts at characterization were unsuccessful.

Orthogonal tandem catalysis has been applied to allylicisomerization-RCM, using a Pd–PPh3 isomerization catalystin conjunction with2b as metathesis catalyst (Scheme 22)


Scheme 22. Orthogonal tandem catalysis in allylic acetate isomerization-RCM; dba: dibenzylideneacetone[81].

[81]. Competing RCM of the starting allylic acetates is notapparently observed. The failure of the corresponding reac-tion utilizing 1a as RCM catalyst[82] exemplifies the dif-ficulty in balancing opposing catalyst requirements in or-thogonal catalysis. In this case, either allylic isomerizationor RCM could be induced, but not both, an observation at-tributed to deactivation of1a by added PPh3 (required to sta-bilize the Pd catalyst), or poisoning of the PPh3-free Pd(0)reagent by the PCy3 liberated by activation of1a.

3.2.4. Metathesis-Heck couplingSimilar difficulties are encountered in attempts to cou-

ple Ru-catalyzed RCM and Pd-catalyzed Heck reactions inan orthogonal catalysis approach to construction of bridgedrings (Scheme 23) [83,84]. The RCM reaction was carriedout at room temperature, following which the mixture washeated to initiate Heck coupling. While satisfactory yieldscould be obtained where five-membered rings were formedin the RCM step, Heck catalysis predominated for largerring sizes, presumably due to the slower rate of RCM andcompetitive poisoning of1a by phosphine or Pd. (Notably,poisoning of the RCM reaction was found even in the pres-ence of phosphine-free Pd(OAc)2). Improved results werefound on use of a polymer-supported Pd catalyst, in whichaccess to the Pd sites is thought to be promoted only at thehigher temperatures used for the Heck chemistry, or on useof a fluorous biphasic solvent system capable of sequester-ing the Pd precursor[84].

Scheme 23. Construction of bridged rings via orthogonal tandemRCM-Heck catalysis[83,84].

Scheme 24. Skeletal expansion of unsaturated silyl enol ethers viaauto-tandem hydroformylation–cyclization[86].

3.3. Tandem catalyses involving hydroformylation

The aldehydes obtained by hydroformylation of�-olefinsare commonly transformed into other functionalities: intoalcohols via hydrogenation, carboxylic acids via oxida-tion, amines via hydroamination (aminomethylation), orN-acetylated amino acids via amidocarbonylation[85].Coupled catalytic processes are thus of great interest in thisarea, which is particularly rich in examples of auto-tandemcatalysis. A recent review (highly comprehensive to the endof 1998) described domino or tandem reactions in whichall steps are carried out under hydroformylation conditions[13]. Several dozen examples of tandemcatalysisare in-cluded, the majority of which involve acid or base catalysisin the second cycle. Given this coverage, we shall focuson examples emerging since the beginning of 1999. A fewof these were noted in a 2003 review of methods for con-structing complex organic molecules by reaction sequencesthat include a hydroformylation step[12].

3.3.1. Hydroformylation-Mukaiyama cyclizationAuto-tandem hydroformylation–cyclization, catalyzed by

[RhCl(cod)]2, enables expansion of the organic skeleton ofunsaturated silyl enol ethers (Scheme 24) [86]. Linear alde-hydes generated in the hydroformylation step undergo a sub-sequent Rh-catalyzed, intramolecular Mukaiyama aldol ad-dition. Bicyclic ketones are also accessible from cyclic silylenol ethers.

3.3.2. Hydroformylation–carbonylation(amidocarbonylation)

Derivatives of the steroids androstene and pregnene havebeen transformed directly intoN-acyl amino acids by anorthogonal catalysis procedure utilizing [RhCl(nbd)]2 andCo2(CO)8 (Scheme 25) [87]. The rhodium phosphine cat-alyst (generated in situ in the presence of syn gas andphosphine) effects hydroformylation of the internal olefinto generate aldehyde11. Only in the presence of Co2(CO)8are N-acyl amino acids obtained as the major products.An unstable amidoalcohol intermediate12, formed byreaction of the amide with aldehyde, is proposed to un-dergo cobalt-catalyzed CO insertion to yield the desiredN-acyl amino acid. Observation of unsaturated or satu-rated amidomethylidene products13 or 14 in the absence


Scheme 25. Orthogonal catalysis in the construction of�-amino acidsteroid derivatives[87].

of Co2(CO)8 was ascribed to (reversible) dehydration,followed by Rh-catalyzed hydrogenation of the doublebond where the added phosphine was sufficiently basic.Formation of 14 thus provides an example of undesiredauto-tandem catalysis.

3.3.3. Hydrogenation–hydroformylationCyclic homochiral precursors of biologically important

amino acids have been synthesized using [Rh(cod)(PP)]OTfas catalyst (PP= 2R,5R-Et-DuPHOS), in an elegant exam-ple of assisted tandem catalysis (Scheme 26) [88]. Thus,enantioselective (mono)hydrogenation of diene15 is ef-fected under H2: introduction of syn gas generates a rhodiumcarbonyl species, which catalyzes hydroformylation of theremaining double bond. Spontaneous cyclization of thealdehyde product gives a mixture of five- and six-memberedcyclic amides in >95% e.e. The sequence was also ac-complished (albeit with lower efficiency in Rh utilization)via orthogonal catalysis, using [Rh(cod)(Et-DuPHOS]OTffor the hydrogenation step and [Rh(OAc)2]2/PPh3 or[Rh(OAc)2]2/BIPHEPHOS for hydroformylation. Hydro-genation of the trisubstituted, endocyclic double bond wascarried out in a separate procedure requiring use of Pd/C.Subsequent acid hydrolysis yielded the cyclic�-aminoacids[88].

Scheme 26. Assisted tandem catalysis in conversion of olefins to aminoacid derivatives[88].

Scheme 27. Auto-tandem catalysis in hydroformylation–hydrogenation of�-olefins to alcohols[89].

3.3.4. Hydroformylation–hydrogenationExtremely important in hydroformylation chemistry are

examples of auto-tandem catalysis in which the aldehydicproduct of hydroformylation functions directly as a substratefor hydrogenation, yielding alcohol products. The aldehydecan also, however, undergo stoichiometric modification priorto uptake into the hydrogenation cycle, expanding the rangeof organic products accessible.

3.3.4.1. Alcohol products.A key sequence in the ShellOxo Process (seeSection 3.3.6.1) involves use of aCo-alkylphosphine catalyst to promote both hydroformy-lation of �-olefins, and the ensuing hydrogenation of thealdehyde products to alcohols[43]. In other applications,tandem hydroformylation–hydrogenation of functional-ized alkenes is directed at production of commerciallyimportant diols from unsaturated alcohols, alkynes, di-enes or esters. Oligosilsesquioxane dendrimers bearingRh–alkylphosphine groups are effective in the tandem trans-formation (Scheme 27), but the corresponding arylphos-phine derivatives promote only the hydroformylation step[89].

3.3.4.2. Amine products (hydroaminomethylation).Trans-formation of olefins to homologous amines can be effectedby sequential processes of catalytic hydroformylation, stoi-chiometric trapping with amine or ammonia, and catalyticreduction (Scheme 28). Where the efficiency in metalutilization is high, such auto-tandem catalysis offer an at-tractive alternative to the classical syntheses of amines viaammonolysis of alcohols, reductive amination of aldehy-des, or hydrogenation of nitriles. Complications, however,can emerge from undesired tandem catalytic pathways (iso-merization or hydrogenation of the olefin, aldehyde, or

Scheme 28. Auto-tandem catalysis in hydroaminomethylation of olefins.Intermediates shown for linear product only[90].


imine intermediates), as well as from side-reactions, suchas amine-catalyzed aldol reactions, or incomplete reductionof intermediate imines and enamines[85]. Regioselectivityduring hydroformylation is also critical, as separation oflinear and branched products is often problematic. Good toexcellent yields of linear amines were obtained in a tandemcatalysis protocol applicable to a wide range of olefins andamines, using a Rh-phosphine catalyst generated in situ(Scheme 28) [90]. XANTPHOS afforded regioselectivity inthe hydroformylation step superior to that found with otherchelating or monodentate phosphines, as well as higheractivity in the ensuing enamine hydrogenation.

The low hydroaminomethylation activity of Ru catalystshas been attributed to slow rates of hydroformylation[91].Rhodium catalysis, as indicated above, exhibits higher hy-droformylation activity, but this can be offset by low ac-tivity in the ensuing C=N hydrogenation (an issue exacer-bated by the high cost of Rh). Orthogonal catalysis, involv-ing Rh-catalyzed hydroformylation and Ru-catalyzed C=Nhydrogenation, has been used to prepare a series of aliphaticamines by hydroaminomethylation of 1-hexene, 1-octene or1-dodecene with dimethylamine[85]. Use of Ru(acac)3 inconjunction with Rh(2-ethylhexanoate)3 enables a decreasein rhodium loading from 240 ppm (Rh:olefin) to as low as3 ppm, with high selectivity for the amine product. Irid-ium has likewise been used to accelerate the imine hydro-genation step in orthogonal catalysis procedures based on[RhCl(cod)]2 and [IrCl(cod)]2 [92].

Hydroaminomethylation methodologies have been exten-sively applied to construction of structurally complex or-ganic amines by Eilbracht and co-workers[93–99]. Thiswork has been recently reviewed[13,100]. Substrates withdirected reactivity (e.g. 2,2′ or 3,3′-disubstituted olefins,which favour terminal aldehydes) aid in controlling regios-electivity. Macroheterocycles were prepared in moderate togood yields from diolefins and diamines[101,102]. Like-wise, 20–28 membered azamacroheterocycles have been ob-tained in up to 78% yield by tandem Rh-catalyzed hy-droformylation of aromatic diallyl ethers of hydroquinone,biphenol and binaphthol, followed by reductive aminationof the dialdehydes with�,�-diamines (Scheme 29) [103].

3.3.4.3. C–C skeleton expansion.Expansion of the C–Cskeleton of methallylic alcohol derivatives has been ef-

Scheme 29. Construction of azamacroheterocycles via auto-tandem catal-ysis in hydroaminomethylation of olefins[103] (intermediates analogousto those inScheme 28)

Scheme 30. Auto-tandem catalysis in hydroformylation–Wittig–hydro-genation of methallylic alcohols[104].

fected by stoichiometric Wittig olefination of the aldehydeobtained by Rh-catalyzed hydroformylation, followed byRh-catalyzed reduction of the C=C bond in the product(Scheme 30) [104]. The o-diphenylphosphinobenzoate di-recting group used in this reaction promotessynspecificityin the hydroformylation step.

In a closely analogous tandem catalysis sequence, theWittig olefination step is replaced by a base-catalyzedKnoevenagel condensation with malonates,�-ketoestersand�-diketones (Scheme 31) [105]. This sequence is pre-ferred for its atom economy: in principle, water is the onlybyproduct, whereas the Wittig route generates stoichiomet-ric quantities of triphenylphosphine oxide.

3.3.5. Isomerization–hydroformylationTransformation of internal olefins to linear aldehydes and

aldehyde derivatives is attractive both for the low cost ofthe feedstocks versus�-olefins, and for the value of the lin-ear aldehyde, alcohol, and amine products. Of considerableindustrial interest, therefore, are tandem catalytic processesfor isomerization of internal to�-olefins, followed by hy-droformylation. High rates of isomerization, versus hydro-formylation, are desired in order to favour linear product.Owing to the greater thermodynamic stability of the inter-nal olefins, however,�-olefins typically account for<5% oftotal olefin at equilibrium[106]. High catalyst selectivity isthus required in order to achieve preferential hydroformyla-tion of terminal olefins to linear products. This chemistry of-

Scheme 31. Auto-tandem catalysis in hydroformylation–Knoevenagel–hydrogenation of methallylic alcohols[105].


Scheme 32. Auto-tandem catalysis in isomerization–hydroformylation ofinternal olefins to linear products[107].

fers a challenging opportunity for tandem catalysis, in whichcatalyst design plays a central role.

Rh complexes of the chelating diphosphite BIPHEPHOSeffect efficient tandem isomerization–hydroformylation ofinternal octenes to the industrially desirable C-9 aldehyden-nonanal (Scheme 32) [107]. Use of propylene carbonatesolvent improves selectivity (89–95% yields) as well asthe ease of separating products from the catalyst, whichremains in the propylene carbonate phase for reuse. Aclosely related diphosphite containing a 2,2′-dioxydiphenylfragment affords lower yields (70%) but higher turnoverfrequencies (4600 h−1, versus 34 h−1) [108]. The low ther-mal stability of phosphites, however, coupled with theirhydrolytic sensitivity, may undermine catalyst integrity inmultiple tandem cycles. Chelating diphosphine ligands ex-hibit greater thermal and chemical stability than phosphites,and their rhodium complexes display high regioselectivityfor the linear aldehydes. In comparison to Rh-XANTPHOScomplexes[109], improved isomerization activity is foundfor electron-deficient NAPHOS derivatives (e.g. IPHOS).Turnovers of up to 925 h−1 and yields of ca. 70% were ob-tained in synthesis of linear aldehydes from (e.g.) 2-butene[106].

3.3.6. Double-tandem processes involvinghydroformylation

3.3.6.1. Isomerization–hydroformylation–hydrogenation:alcohol products. The Shell Oxo Process, as noted above,is the most important industrial application of tandemcatalytic methodology. In a beautiful example ofdoubleauto-tandem catalysis, a Co-alkylphosphine catalyst effectsisomerization of internal olefins in the presence of syngas, hydroformylation of the�-olefin products, and hydro-genation of the resulting aldehydes to alcohols[43]. Highchemoselectivity is critical in this reaction sequence, in or-der to effect reduction of the aldehyde without significanthydrogenation of the starting olefin.

3.3.6.2. Isomerization–hydroformylation–hydrogenation:amine products. The isomerization–hydroaminomethy-lation sequence is particularly challenging, even relativeto hydroaminomethylation (vide supra), owing to the sus-ceptibility of the isomerization catalysts to poisoning by�-donor imine and amine products. This transformation has

Scheme 33. (Double) auto-tandem catalysis in isomerization–hydro-aminomethylation of internal olefins to linear amines[110]. Intermediatesshown for linear product only.

Scheme 34. Auto-tandem catalysis in formation of lactones from acrylatesvia sequential, Ru-catalyzed hydroformylation, Michael addition, and hy-drogenation[111].

only recently been accomplished in significant yield, thekey advance emerging from identification of an optimumphosphine ligand (Scheme 33; PP: IPHOS)[110]. Selectiv-ity in these systems is highly sensitive to small variationsin the steric and electronic nature of the phosphine ligands.

3.3.6.3. Hydroformylation–Michael addition–hydrogena-tion. A serendipitous double auto-tandem catalysis re-sulted in formation of lactone17 on attempted hydroformy-lation of methyl acrylate (MA) using a Ru3(CO)12/1,10-phenanthroline catalyst system (Scheme 34) [111]. Simplehydroformylation products were not observed. Instead,sequential hydroformylation of methyl acrylate, Michaeladdition of the aldehyde and MA, and hydrogenation ofaddition product16 (all three steps being Ru-catalyzed), fol-lowed by spontaneous cyclization, yields lactone17 as thesole carbonylated product. For the corresponding reactionwith Ru3(CO)12/PPh3, the dominant pathway is competinghydrogenation of the acrylate C=C bond, again illustratingthe challenges in balancing competing catalytic pathwaysin auto-tandem catalysis.

4. Conclusions

The past few years have seen an explosion in the develop-ment and application of tandem catalysis. Further advances


will be driven by the continuously expanding importanceof transition metal catalysis in organic synthesis, and thepotential of tandem catalysis to achieve higher molecularcomplexity while limiting catalyst and process costs. Theparallel investment of effort in organic reaction design, andin deconvoluting the inorganic/organometallic chemistry un-derlying catalyst transformation, will offer key opportuni-ties for the development of sophisticated synthetic strategiesincorporating new tandem catalyses.

Acknowledgements

Stimulating discussions with Profs. James Green, LisaRosenberg, Marc Snapper, and Bob Crabtree were greatlyappreciated. Prof. James Gleason is thanked for sharing a re-view on tandem catalysis prior to publication, and the Brazil-ian Conselho de Desenvolvimento Cientifico e Tecnologico(CNPq) for a sabbatical fellowship to ES. This work wassupported by the Natural Sciences and Engineering ResearchCouncil of Canada, the Canada Foundation for Innovation,and the Ontario Innovation Trust.

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